HHIP-like protein 1 (HHIPL1), also known as HHIP2, is aprotein that in humans is encoded by theHHIPL1 gene onchromosome 14.[5] It is not significantly expressed in many tissues and cell types,[6] though HHIPL1mRNA has been detected intrabecular bone cells.[7] Little is known about the precise biological function of HHIPL1, but the protein has been linked toadenomas.[8] TheHHIPL1 gene also contains one of 27SNPs associated with increased risk ofcoronary artery disease.[9]
This protein belongs to theHHIP family and is one of three members found in humans.[10] HHIPL1 contains a SRCRdomain and anN-terminalsignal peptide.[7][10]Processing of the signal peptide leads to this protein'ssecretion. As an HHIP member, it also contains a conserved HHIP-homologous (HIPH) domain composed of 18cysteineresidues.[7]
The function of HHIPL1 is not known. The section below refers to the function of HHIP.
The function of HHIP is not well known but has been shown to be tightly associated with lung function. Knocking out HHIP in mice is neonatally lethal due to defective branching in the lung.[11][12] The heterozygous knockout of HHIP has been shown to contribute to more severeemphysema induced by cigarette smoke compared to wild type mice.[13] Furthermore, increased spontaneous emphysema andoxidative stress levels have been found in the lungs of HHIPheterozygous mice.[14] Both the expression level and enhancer activity of HHIP is reduced inchronic obstructive pulmonary disease (COPD) lungs, suggesting a protective role of HHIP in COPD pathogenesis.[15]
DNA methylation is one of several epigenetic modifications recognized as hallmarks of tumorigenesis. In a genome-wide survey of subtype-specific epigenomic changes in adenoma, the HHIPL1 gene was hypermethylated in 12 of 13 non-functioning (NF) adenomas, as well as in growth hormone (GH)- and prolectin-secreting adenomas. Thus, HHIPL1 has the potential to serve as a biomarker to predict or characterise tumorous growth patterns.[8] Unlike another member of the human HHIP gene family, HHIP, which is regarded as a pharmacogenomics target in the fields of oncology and vascular medicine, HHIPL1 has yet been reported with such potential.[7]
Additionally, in the cardiovascular field, HHIPL1 has been associated with CAD in Europeans, South Asians, and a population of Japanese.[16][17] However, in another study based on a Japanese population, the association failed to be replicated, suggesting that this association is population-specific.[18]
A multi-locus genetic risk score study based on a combination of 27 loci, including the HHIFL1 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[9]
